Heparin prodrugs and drug delivery stents formed therefrom

ABSTRACT

A prodrug comprising a heparin and a drug is provided. The prodrug can be used to form a coating on a medical device. The prodrug can also be used with a polymeric material to form a coating on a medical device. The polymeric material can be a hydrophobic polymer, a hydrophilic polymer, a non-fouling polymer, or combinations thereof. The medical device can be implanted in a human being for the treatment of a disease such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. application Ser.No. 10/871,658 filed on Jun. 18, 2004, the teaching of which isincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

This invention generally relates to a prodrug formed of heparin and adrug and drug-delivery stents formed from a material having the prodrug.

DESCRIPTION OF THE BACKGROUND

Blood has a property of being coagulated by the action of variouscomponents in blood when it has come into contact with foreign matters.Hence, there is a need for a high anticoagulant property in componentmaterials for medical articles or instruments used on the part cominginto contact with blood, as exemplified by artificial hearts, artificialcardiac valves, artificial blood vessels, blood vessel catheters,cannulas, pump-oxygenators, blood vessel by-pass tubes, intraaorticballoon pumps, transfusion instruments and extracorporeal circulationcircuits.

Heparin has been commonly used to impart to anticoagulant properties themedical devices, but a systemic use of heparin may undesirably lead tothe formation of a large number of bleeding nests. Methods have beendeveloped to minimize side effects associated with the use of heparinwith limited success (see, for example, U.S. Pat. Nos. 5,270,064 and6,630,580). Meanwhile, problems associated with systemic administrationof a drug have led to the development of methods for local delivery ofthe drug. Administration of a pharmacologically active drug directly toa patient may lead to some undesirable consequences because manytherapeutic drugs have undesirable properties that may becomepharmacological, pharmaceutical, or pharmacokinetic barriers in clinicaldrug applications.

Therefore, in the art of drug-delivery implantable medical devices,there is a need for minimizing the side effects associated with the useof heparin and a drug.

The present invention addresses such problems by providing a coatingcomposition and a coating formed thereof including a prodrug formed ofheparin and a drug.

SUMMARY OF THE INVENTION

Provided herein is a prodrug having heparin and a drug in which the drugand heparin form a hydrolytically or enzymatically unstable linkage. Theprodrug can be an ester type prodrug in which the drug molecule and theheparin molecule can form an ester bond formed of the carboxyl group inthe heparin molecule and hydroxyl group in the drug or vice versa. Theprodrug can be a Schiff-base-type prodrug in which a drug having anamine group and heparin functionalized to have an aldehyde group form aSchiff base or vice versa. The prodrug can also be an acetal- orhemi-acetal-type prodrug in which hydroxyl groups on a drug and heparinfunctionalized to have an aldehyde group or vice versa form an acetal orhemi-acetal.

The prodrug molecule can be used to form a coating on an implantabledevice. The prodrug can also be attached to a polymer via the heparinmolecule to form a polymer bearing the prodrug defined herein, which canthen be coated onto an implantable device. Alternatively, the prodrugcan be grafted onto a polymeric coating on an implantable device.

In one embodiment, the prodrug can be used alone to form a coating on amedical device. In another embodiment, the prodrug can be used with apolymeric material to form a coating on a medical device. The polymericmaterial can be a hydrophobic polymer, a hydrophilic polymer, anon-fouling polymer, or combinations thereof. The medical device can beimplanted in a human being for the treatment of a disease such asatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, or combinations thereof.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows heparin's building blocks: glycosamine and iduronic acid.

DETAILED DESCRIPTION Prodrugs Including Heparin

Many therapeutic drugs have undesirable properties that may becomepharmacological, pharmaceutical, or pharmacokinetic barriers in clinicaldrug applications. Among the various approaches to minimize theundesirable drug properties while retaining the desirable therapeuticactivity, a chemical approach using drug derivatization offers perhapsthe highest flexibility and has been demonstrated as an important meansof improving drug efficacy. The prodrug approach, a chemical approachusing reversible derivatives, can be useful in the optimization of theclinical application of a drug. The prodrug approach gained attention asa technique for improving drug therapy in the early 1970s. Numerousprodrugs have been designed and developed since then to overcomepharmaceutical and pharmacokinetic barriers in clinical drugapplication, such as low oral drug absorption, lack of site specificity,chemical instability, toxicity, and poor patient acceptance (bad taste,odor, pain at injection site, etc.) (Stella V., Pro-drugs: an overviewand definition. In: Higuchi T., Stella V., eds. Prodrugs As Novel DrugDelivery Systems. ACS Symposium Series. Washington, D.C.: AmericanChemical Society; 1975:1-115).

As used herein, the term “prodrug” refers to an agent rendered lessactive by a chemical or biological moiety, which metabolizes into orundergoes in vivo hydrolysis to form a drug or an active ingredientthereof. The term “prodrug” can be used interchangeably with terms suchas “proagent”, “latentiated drugs,” “bioreversible derivatives,” and“congeners” (Harper N J. Drug latentiation. Prog Drug Res. 1962;4:221-294; Roche E B. Design of Biopharmaceutical Properties throughProdrugs and Analogs. Washington, D.C.: American PharmaceuticalAssociation; 1977; Sinkula A A, Yalkowsky S H. Rationale for design ofbiologically reversible drug derivatives: prodrugs. J Pharm Sci. 1975;64:181-210). Usually, the use of the term implies a covalent linkbetween a drug and a chemical moiety, though some authors also use it tocharacterize some forms of salts of the active drug molecule. Althoughthere is no strict universal definition for a prodrug itself, and thedefinition may vary from author to author, generally prodrugs can bedefined as pharmacologically inert chemical derivatives that can beconverted in vivo, enzymatically or nonenzymatically, to the active drugmolecules to exert a therapeutic effect (Sinkula A A, Yalkowsky S H.Rationale for design of biologically reversible drug derivatives:prodrugs. J Pharm Sci. 1975; 64:181-210; Stella V J, Charman W N,Naringrekar V H. Prodrugs. Do they have advantages in clinical practice?Drugs. 29:455-473 (1985)).

In one embodiment, the prodrug described herein includes a drug andheparin that form a linkage that can be enzymatically or hydrolyticallycleaved under in vivo conditions. In some embodiments, the linkage canbe an ester group, a Schiff base, or an acetal or hemi-acetal.

In another embodiment, the prodrug described herein can include a drug,a polymer and heparin. Heparin is conjugated or linked to the polymer bya physical or chemical linkage. The drug can link or be attached to theheparin or the polymer. In some embodiments, the linkage between heparinand the polymer can be, for example, ionic bonding, hydrogen bonding, ora chemical bonding such as an ester group, a Schiff base, or an acetalor hemi-acetal. The linkage between the drug and the polymer can be, forexample, an ester group, a Schiff base, or an acetal or hemi-acetal, andthe linkage between the drug and heparin can be, for example, an estergroup, a Schiff base, or an acetal or hemi-acetal.

Heparin

The term “heparin” refers to a heparin molecule, a heparin fragment suchas pentasaccharide, a heparin derivative or a heparin complex. Heparinderivatives can be any functional or structural variation of heparin.Representative variations include alkali metal or alkaline-earth metalsalts of heparin, such as sodium heparin (e.g., hepsal or pularin),potassium heparin (e.g., clarin), lithium heparin, calcium heparin(e.g., calciparine), magnesium heparin (e.g., cutheparine), lowmolecular weight heparin (e.g., ardeparin sodium) with a molecularweight of from about 4,000 to about 5,000 Daltons and high affinityheparin (see, e.g., Scully, et al., Biochem. J. 262:651-658 (1989)).Other examples include heparin sulfate, heparinoids, heparin basedcompounds and heparin having a hydrophobic counter-ion such astridodecylmethylammonium and benzalkonium.

Heparin contains both carboxyl groups and hydroxyl groups (FIG. 1).Carboxyl groups can form an ester linkage by reacting with hydroxylreactive groups on a drug (see Scheme 1, below). Alternatively, thehydroxyl groups on heparin can also form an ester linkage by reactingwith carboxyl groups on a drug (see Scheme 2, below).

In some other embodiments, the prodrug described herein can be formed ofa functionalized heparin and a drug molecule. For example, Heparin-CHOcan react with an amine group on a drug or vice versa to form aSchiff-base-type prodrug (see Scheme 3, below). Heparin-CHO can alsoreact with hydroxyl groups on a drug or vice versa to form acetal orhemi-acetal type prodrugs (see Scheme 4, below).

Modification of Heparin

Heparin is a highly negatively charged molecule very soluble in water.It has some solubility in formamide, but is practically insoluble inother organic solvents. This lack of solubility in organic solventslimits its use in certain applications. The conventional method ofimproving the solubility of heparin in organic solvents can be achievedby complexing heparin with a positive charged organic moiety such as aquaternary ammonium salt, e.g. tridodecylmethylammoniumchloride andbenzalkonium chloride. Some exemplary, useful hydrophobic quaternaryammonium compounds and methods of forming complexes of these compoundswith heparin are described in U.S. Pat. Nos. 4,654,327, 4,871,357 and5,047,020.

Heparin contains many reactive groups such as carboxyl, amine, andhydroxyl groups in its molecular structure. Partially oxidized heparincontains terminal aldehyde groups. Prior to or subsequent to forming theprodrug described above, in some embodiments, heparin can be physicallyor chemically (e.g. covalently) attached to hydrophilic and hydrophobicpolymers by chemical reactions between the functional groups on heparinand the polymer. Heparin can also be copolymerized with other monomer(s)to form a polymer containing heparin. In some other embodiments,attachment of heparin can be accomplished by chemically (e.g.covalently) or physically coupling heparin onto a polymer-coatedsurface. Physical coupling includes, for example, ionic interaction orhydrogen bonding.

As used herein, the term “hydrophobic” refers to an attribute of amaterial that defines the degree of water affinity of the molecules ofthe material. Hydrophobicity and hydrophilicity are relative terms.Generally, hydrophobicity and hydrophilicity of a polymer can be gaugedusing the Hildebrand solubility parameter δ. The term “Hildebrandsolubility parameter” refers to a parameter indicating the cohesiveenergy density of a substance. The δ parameter is determined as follows:δ=(ΔE/V)^(1/2)where δ is the solubility parameter, (cal/cm³)^(1/2);ΔE is the energy of vaporization, cal/mole; andV is the molar volume, cm³/mole.

If a blend of hydrophobic and hydrophilic polymer(s) is used, whicheverpolymer in the blend has a lower δ value compared to the δ value of theother polymer in the blend is designated as a hydrophobic polymer, andthe polymer with a higher δ value is designated as a hydrophilicpolymer. If more than two polymers are used in the blend, then each canbe ranked in order of its δ value. In some embodiments, the definingboundary between hydrophobic and hydrophilic can be set at 10.5,(cal/cm³)^(1/2).

Any biocompatible polymer can be used to modify the hydrophilicity ofheparin. Representative hydrophobic polymers include, but are notlimited to, poly(ester amide), polystyrene-polyisobutylene-polystyreneblock copolymer (SIS), polystyrene, polyisobutylene, polycaprolactone(PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylacticacid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylene,polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate,poly(trimethylene carbonate), poly(ortho ester), polyphosphazenes,poly(phosphoester), poly(tyrosine derived arylates), poly(tyrosinederived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride(PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane,poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP),poly(vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE),poly(methacrylates) such as poly(butyl methacrylate) (PBMA) orpoly(methyl methacrylate) (PMMA), poly(vinyl acetate),poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol),poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes),poly(silicone-urethanes), poly(urea-urethanes) or a combination thereof.Methods of derivatizing heparin with hydrophobic materials or polymersare described in, for example, U.S. Pat. Nos. 4,331,697; 5,069,899;5,236,570; 5,270,046; 5,453,171; 5,741,881; 5,770,563; 5,855,618;6,589,943 and 6,630,580.

Any hydrophobic counter ion can be used to modify the hydrophilicity ofheparin. For example, hydrophobic quaternary ammonium compounds havebeen commonly used to form complexes with heparin that are soluble inorganic solvents. Some exemplary useful hydrophobic quaternary ammoniumcompounds and methods of forming complexes of these compounds withheparin are described in U.S. Pat. Nos. 4,654,327, 4,871,357 and5,047,020.

In some other embodiments, a hydrophilic polymer and/or a non-foulingpolymer can be used to modify the hydrophilicity of heparin. Non-foulingor anti-fouling is defined as preventing, delaying or reducing theamount of formation of protein build-up caused by the body's reaction toforeign material. Representative hydrophilic polymers include, but arenot limited to, polymers and co-polymers of PEG acrylate (PEGA), PEGmethacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinylpyrrolidone (VP), carboxylic acid bearing monomers such as methacrylicacid (MA), acrylic acid (AA), hydroxyl bearing monomers such as HEMA,hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, and3-trimethylsilylpropyl methacrylate (TMSPMA), poly(ethylene glycol)(PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG,polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS-PEG, PVDF-PEG,PLURONIC™ surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), poly(L-lysine-ethylene glycol) (PLL-g-PEG),poly(L-g-lysine-hyaluronic acid) (PLL-g-HA), poly(L-lysine-g-phosphorylcholine) (PLL-g-PC), poly(L-lysine-g-vinylpyrrolidone) (PLL-g-PVP),poly(ethylimine-g-ethylene glycol) (PEI-g-PEG),poly(ethylimine-g-hyaluronic acid) (PEI-g-HA),poly(ethylimine-g-phosphoryl choline) (PEI-g-PC), andpoly(ethylimine-g-vinylpyrrolidone) (PEI-g-PVP), PLL-co-HA, PLL-co-PC,PLL-co-PVP, PEI-co-PEG, PEI-co-HA, PEI-co-PC, and PEI-co-PVP, hydroxyfunctional poly(vinyl pyrrolidone), polyalkylene oxide, dextran,dextrin, sodium hyaluronate, hyaluronic acid, elastin, chitosan, acrylicsulfate, acrylic sulfonate, acrylic sulfamate, methacrylic sulfate,methacrylic sulfonate, methacrylic sulfamate and combination thereof.The non-fouling polymer can be, for example, poly(ethylene glycol),poly(alkylene oxide), hydroxyethylmethacrylate (HEMA) polymer andcopolymers, poly(n-propylmethacrylamide), sulfonated polystyrene,hyaluronic acid, poly(vinyl alcohol), poly(N-vinyl-2-pyrrolidone),sulfonated dextran, phosphoryl choline, choline, or combinationsthereof.

The heparin can be readily attached to a polymer or polymeric surface byforming a Schiff base between an amino group and an aldehyde group thatheparin and the polymer may have, by forming an amide group between anamine group on a polymer and the carboxyl group on heparin via NHS(N-hydroxysuccinimide) activation (see, e.g., Staros, et al., Anal.Biochem. 156:220-222 (1986)), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) activation (see, e.g., J. M. Tedder, A.Nechvatal, A. W. Murray, et al. Amino-acids and proteins. In: Basicorganic chemistry. London: John Wiley & Sons, Chapter 6, pp. 305-342(1972); D. Sehgal, I. K. Vijay, Anal. Biochem. 218:87 (1994)) oraziridine chemistry. Some representative methods of attaching heparin toa polymer or polymeric surface are described in U.S. application Ser.No. 10/857,141, filed on May 27, 2004, the teachings of which areincorporated herein by reference.

In a further embodiment, heparin can be derivatized with an unsaturatedgroup such as acrylate, e.g., methacrylate, or vinyl alcohol using thechemistry described above. The heparin functionalized with anunsaturated group can be used in a free radical polymerization to graftor crosslink to a substrate or another formulation component such as apolymer.

Drugs

The drug can be any agent which is biologically active and capable offorming an ester bond with the carboxyl group or hydroxyl group of theheparin molecule or capable of forming a Schiff base or acetal orhemi-acetal with heparin functionalized to have an aldehyde group. Inthe alternative, the drug can have an aldehyde so as to react with theamino group of heparin-NH₂ to form a Schiff base prodrug or an aldehydeor keto group so as to react with the hydroxyl group or groups onheparin to acetal or hemi-acetal prodrug. Most drugs have one ofhydroxyl, carboxyl, amino, keto or aldehyde groups and thus can form theprodrugs described herein.

The drug can be, for example, a therapeutic, prophylactic, or diagnosticagent. As used herein, the drug includes a bioactive moiety, derivative,or metabolite of the drug.

Examples of suitable therapeutic and prophylactic agents capable offorming the prodrugs described herein include synthetic inorganic andorganic compounds, proteins and peptides, polysaccharides and othersugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Nucleic acidsequences include genes, antisense molecules which bind to complementaryDNA to inhibit transcription, and ribozymes. Other examples of drugsinclude antibodies, receptor ligands, and enzymes, adhesion peptides,oligosaccharides, blood clotting factors, inhibitors or clot dissolvingagents such as streptokinase and tissue plasminogen activator, antigensfor immunization, hormones and growth factors, oligonucleotides such asantisense oligonucleotides and ribozymes and retroviral vectors for usein gene therapy,

In one embodiment, the drug can be a drug for inhibiting the activity ofvascular smooth muscle cells. More specifically, the drug can be aimedat inhibiting abnormal or inappropriate migration and/or proliferationof smooth muscle cells for the inhibition of restenosis. The drug canalso include any substance capable of exerting a therapeutic orprophylactic effect in the practice of the present invention. Forexample, the drug can be a prohealing drug that imparts a benignneointimal response characterized by controlled proliferation of smoothmuscle cells and controlled deposition of extracellular matrix withcomplete luminal coverage by phenotypically functional (similar touninjured, healthy intima) and morphologically normal (similar touninjured, healthy intima) endothelial cells. The drug can also fallunder the genus of antineoplastic, cytostatic or anti-proliferative,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.),docetaxel (e.g. Taxotere®, from Aventis S.A., Frankfurt, Germany)methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn,Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers SquibbCo., Stamford, Conn.). Examples of such antiplatelets, anticoagulants,antifibrin, and antithrombins include heparinoids, hirudin, argatroban,forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist, antibody,recombinant hirudin, and thrombin inhibitors such as Angiomax ä (Biogen,Inc., Cambridge, Mass.). Examples of cytostatic or antiproliferativeagents include angiopeptin, angiotensin converting enzyme inhibitorssuch as captopril (e.g. Capoten® and Capozide® from Bristol-Myers SquibbCo., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® andPrinzide® from Merck & Co., Inc., Whitehouse Station, N.J.), actinomycinD, or derivatives and analogs thereof (manufactured by Sigma-Aldrich1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGENavailable from Merck). Synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin I₁, actinomycin X₁, and actinomycin C₁.Other drugs include calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. Anexample of an antiallergic agent is permirolast potassium.

Other therapeutic substances or agents which may be appropriate includealpha-interferon, genetically engineered epithelial cells, antibodiessuch as CD-34 antibody, abciximab (REOPRO), and progenitor cellcapturing antibody, prohealing drugs that promotes controlledproliferation of muscle cells with a normal and physiologically benigncomposition and synthesis products, enzymes, anti-inflammatory agents,antivirals, anticancer drugs, anticoagulant agents, free radicalscavengers, estradiol, steroidal anti-inflammatory agents, non-steroidalanti-inflammatory, antibiotics, nitric oxide donors, super oxidedismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus,dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,ABT-578, clobetasol, cytostatic agents, aspirin, and a combinationthereof.

The foregoing substances are listed by way of example and are not meantto be limiting. Other active agents which are currently available orthat may be developed in the future are equally applicable.

The dosage or concentration of the drug required to produce a favorabletherapeutic effect should be less than the level at which the drugproduces toxic effects and greater than the level at whichnon-therapeutic results are obtained. The dosage or concentration of thedrug can depend upon factors such as the particular circumstances of thepatient, the nature of the trauma, the nature of the therapy desired,the time over which the ingredient administered resides at the vascularsite, and, if other active agents are employed, the nature and type ofthe substance or combination of substances. Therapeutic effectivedosages can be determined empirically, for example by infusing vesselsfrom suitable animal model systems and using immunohistochemical,fluorescent or electron microscopy methods to detect the agent and itseffects, or by conducting suitable in vitro studies. Standardpharmacological test procedures to determine dosages are understood byone of ordinary skill in the art.

Method of Forming a Prodrug

The carboxylic acid group of the heparin molecule can form an ester bondwith a drug molecule via an established procedure in the art of organicsynthesis (see, for example, Larock, Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, John Wiley &Sons, Inc., Copyright 1999). Generally, the prodrug described herein canbe prepared according to Scheme 1, as described below.

In Scheme 1, R represents a drug molecule or a derivative thereof.Heparin represents a heparin molecule or a moiety or derivative thereof.X represents a leaving group attached to the drug molecule. For example,X can be OH, a halo group, mesylate or tosyl group, and any other groupscapable of leaving the drug molecule in forming the drug/heparin esterbond.

Alternatively, the prodrug can be made via a hydroxyl group in theheparin molecule and a carboxylic acid, as shown in Scheme 2.

In Scheme 2, R represents a drug molecule or a derivative thereof.Heparin represents a heparin molecule or a moiety or derivative thereof.X represents a leaving group attached to the carboxyl group of the drugmolecule. For example, X can be H, a halo group, a carboxylate, mesylateor tosyl group, or any other group capable of leaving the drug moleculein forming the drug/heparin ester bond.

In some other embodiments, the prodrug described herein can be formedvia an imine Schiff base by Heparin-CHO with an amine-containing drug(Scheme 3) or vice versa (Scheme 4). As shown in Scheme 3, the aldehydegroup of Heparin-CHO can react with the amine group of anamine-containing drug to form an imine Schiff base, which ishydrolytically unstable and can release the amine-containing drug underin vivo conditions. Scheme 4 shows an alternative strategy for formingthe prodrug by the reaction of the amino group of Heparin-NH₂ with aketo group on the drug molecule to form an imine Schiff base linkage.

In still some other embodiments, the prodrug described herein can beformed via an acetal or hemi-acetal by heparin-CHO with a hydroxyl groupor hydroxyl groups on a drug (Scheme 5) or vice versa (Scheme 6). Theacetal or hemi-acetal can undergo hydrolysis under in vivo conditions torelease the drug. As shown in Scheme 5, the aldehyde group ofheparin-CHO can react with the hydroxyl group or groups on a drug toform a prodrug with an acetal linkage or hemi-acetal linkage (Scheme 5).Alternatively, the hydroxyl group or groups can react with an aldehydeor keto group on a drug to form a prodrug with an acetal linkage orhemi-acetal linkage (Scheme 6).

In one embodiment, the hydroxyl group on the C40 position of everolimuscan react with the carboxyl group on heparin to form an ester bond so asto form an everolimus/heparin prodrug.

In another embodiment, a drug can form a prodrug with heparin attachedto a polymer such as poly(L-lysine-g-ethylene glycol) (PLL-PEG), whichcan be PLL-g-PEG or PLL-co-PEG. In this embodiment, the amino group inthe PLL-PEG can react with a carboxyl group in heparin to form an amidebond via EDC activation and/or NHS activation, as described above.Alternatively, the amino group in the PLL-PEG can react with heparin-CHOto form a Schiff base. A drug such as paclitaxel, docetaxel, oreverolimus can then be attached or linked to the heparin via one of thefunctionalities, such as an amino group, an aldehyde group, a carboxylgroup or a hydroxyl group to form a prodrug as per the abovedescription. In addition to heparin, the point of attachment for thedrug can also be the PLL backbone via NH₂ groups on PLL or PEG via aterminal hydroxyl group, an amino group or an aldehyde group of PEG.Using the same strategy, in some other embodiments, prodrugs can beformed by a drug and a polymer such as poly(L-lysine-hyaluronic acid)(PLL-HA), poly(L-lysine-phosphoryl choline) (PLL-PC),poly(L-lysine-vinylpyrrolidone) (PLL-PVP), poly(ethylimine-ethyleneglycol) (PEI-PEG), poly(ethylimine-hyaluronic acid) (PEI-HA),poly(ethylimine-phosphoryl choline) (PEI-PC), andpoly(ethylimine-vinylpyrrolidone) (PEI-PVP). These PLL or PEI basedcopolymers can be graft or block copolymers, e.g., PLL-g-PEG, PLL-g-HA,PLL-g-PC, PLL-g-PVP, PEI-g-PEG, PEI-g-HA, PEI-g-PC, PEI-g-PVP,PLL-co-HA, PLL-co-PC, PLL-co-PVP, PEI-co-PEG, PEI-co-HA, PEI-co-PC, andPEI-co-PVP. Note, in still some other embodiments, the primary amine—NH₂ groups in PLL or PEI can be converted to NH₃ ⁺ ions on the polymerunder an acidic pH to bind or link with heparin.

Coatings Having a Prodrug

The prodrug can be used to form a coating on an implantable device. Theprodrug can also be attached to a polymer via the heparin molecule toform a polymer bearing the prodrug defined herein, which can then becoated onto an implantable device. Alternatively, the prodrug can beattached or grafted onto a polymeric coating on an implantable device.

The prodrug provided herein can be used alone to form a coating on amedical device. The prodrug can also be used in combination with apolymeric material. The prodrug can be blended with a polymeric coatingmaterial or deposited as a coating on top of a polymeric coating whichitself may optionally include a drug. The polymeric material can be anybiocompatible polymer such as a hydrophobic polymer, a hydrophilicpolymer, a non-fouling polymer, or a combination thereof. The polymericmaterial can be biodegradable, bioerodable, bioabsorable or biodurable.

In one embodiment, the coating material is a hydrophobic polymer.Representative hydrophobic polymers include, but are not limited to,polystyrene-polyisobutylene-polystyrene block copolymer (SIS),polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide),poly(D,L-lactide), poly(lactides), polylactic acid (PLA),poly(lactide-co-glycolide), poly(glycolide), polyalkylene,polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate,poly(trimethylene carbonate), poly(ortho ester), polyphosphazenes,poly(phosphoester), poly(tyrosine derived arylates), poly(tyrosinederived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride(PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane,poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP),poly(vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE),poly(butyl methacrylate), poly(methyl methacrylate),poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinylacetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes),poly(ether-urethanes), poly(carbonate-urethanes),poly(silicone-urethanes), poly(2-hydroxyethyl methacrylate),poly(urea-urethanes) and a combination thereof.

In one embodiment, the coating material is a hydrophilic polymer, suchas those previously described. In some embodiments, hydrophilic polymersinclude, but are not limited to, polymers and co-polymers of PEGacrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), hydroxyl bearing monomers such as HEMA, hydroxypropylmethacrylate (HPMA), hydroxypropylmethacrylamide, and3-trimethylsilylpropyl methacrylate (TMSPMA), poly(ethylene glycol)(PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG,polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS-PEG, PVDF-PEG,PLURONIC™ surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),polyalkylene oxide, dextran, dextrin, sodium hyaluronate, hyaluronicacid, elastin, chitosan, acrylic sulfate, acrylic sulfonate, acrylicsulfamate, methacrylic sulfate, methacrylic sulfonate, methacrylicsulfamate or combination thereof.

In another embodiment, the coating material is a non-fouling polymersuch as, for example, poly(ethylene glycol), poly(alkylene oxide),hydroxyethylmethacrylate (HEMA) polymer and copolymers,poly(n-propylmethacrylamide), sulfonated polystyrene, hyaluronic acid(HA), poly(vinyl alcohol), poly(N-vinyl-2-pyrrolidone), sulfonateddextran, phospholipids such as phosphoryl choline (PC) and choline, orcombinations thereof.

Examples of Implantable Device

As used herein, an implantable device may be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corporation, Santa Clara, Calif.). The underlying structureof the device can be of virtually any design. The device can be made ofa metallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention.

Method of Use

In accordance with embodiments of the invention, a coating of thevarious described embodiments can be formed on an implantable device orprosthesis, e.g., a stent. For coatings including one or more activeagents, the agent will retain on the medical device such as a stentduring delivery and expansion of the device, and be released at adesired rate and for a predetermined duration of time at the site ofimplantation. Preferably, the medical device is a stent. A stent havingthe above-described coating is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coating isparticularly useful for treating occluded regions of blood vesselscaused by abnormal or inappropriate migration and proliferation ofsmooth muscle cells, thrombosis, and restenosis. Stents may be placed ina wide array of blood vessels, both arteries and veins. Representativeexamples of sites include the iliac, renal, and coronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A coating composition comprising: a prodrug, theprodrug comprising a drug, heparin, and a first polymer, wherein theheparin is linked covalently to the first polymer and the drug, whereinthe covalent linkage between the drug and the heparin is eitherhydrolytically or enzymatically unstable, wherein the drug is notpharmacologically active when linked to the heparin, and wherein thefirst polymer is selected from the group consisting ofpoly(L-lysine-co-hyaluronic acid) (PLL-co-HA),poly(L-lysine-co-phosphoryl choline) (PLL-co-PC),poly(ethylimine-co-hyaluronic acid) (PEI-co-HA),poly(ethylimine-co-phosphoryl choline) (PEI-co-PC),poly(L-lysine-g-hyaluronic acid) (PLL-g-HA), poly(L-lysine-g-phosphorylcholine) (PLL-g-PC), poly(ethylimine-g-hyaluronic acid) (PEI-g-HA), andpoly(ethylimine-g-phosphoryl choline) (PEI-g-PC).
 2. The composition ofclaim 1, wherein the drug is selected from the group consisting ofantiproliferative, anti-inflammatory, non-steroidal anti-inflammatory,and antimitotic drugs and combinations thereof.
 3. The composition ofclaim 2, wherein the drug is selected from the group consisting ofpaclitaxel, docetaxel, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,(ABT-578, zotarolimus) and combinations thereof.
 4. The composition ofclaim 3, wherein the heparin is a pentasaccharide.
 5. The composition ofclaim 3, further comprising a second polymer selected from the groupconsisting of a hydrophilic polymer, a hydrophobic polymer, anon-fouling polymer, and combinations thereof.
 6. The composition ofclaim 1, wherein the drug is linked directly to the first polymer. 7.The composition of claim 1, wherein the heparin is a pentasaccharide. 8.The composition of claim 7, further comprising a second polymer selectedfrom the group consisting of a hydrophilic polymer, a hydrophobicpolymer, a non-fouling polymer, and combinations thereof.
 9. Thecomposition of claim 1, further comprising a second polymer selectedfrom the group consisting of a hydrophilic polymer, a hydrophobicpolymer, a non-fouling polymer, and combinations thereof.